The present invention relates generally to compounds having a cyclopentabenzofuran core. More particularly, the present invention relates to cyclopentabenzofuran compounds having a bulky substituent at the 6-oxy position, such as where the cyclopentabenzofuran core is substituted by a dioxanyloxy moiety. The invention also relates to the use of these compounds in therapy and compositions comprising said compounds.
Aglaia is a large genus of the family Meliaceac comprising over 100 (mostly woody) species in Indo-Malaysia and the Western Pacific region. Uses include treatment of fever, fractures, parturition and inflammation. Extracts are also used as bactericides, insecticides, in perfumery, as an astringent, tonic, a refrigerant (Dr Duke""s Phytochemical and Ethnobotanical Databases) and for the treatment of abdominal tumours (Pannel, et al, 1992, Kew Bull., (16) 273-283).
More recently, a number of 1H-cyclopenta[b]benzofuran lignans have been isolated from Aglaia species (see for example, WO97/08161; JP 97171356; Ohse, et al, J Nat Prod, 1996, 59(7):650-52; Lee et al, Chem. Biol. Interact., 1998, 115(3):215-28; Wu et al, J. Nat. Prod., 1997, 60(6):606-08; Bohnenstengel et al, Z. Naturforsch, 1999, 54c (12):55-60 and Bohnenstengel et al, Z. Naturforsch, 1999, 54c (12):1075-83, Xu, Y. J., et al, 2000, J. Nat. Prod., 63, 4732-76, the entire contents of which are incorporated herein by reference). A number of these compounds have also been noted for their insecticidal activity (Janpraseri, et al, 1993, Phytochemistry, 32 (1): 67-69; Ishibashi et al, 1993, Phytochemistry, 32 (2): 307-310; Hiort, et al, 1999, J. Nat. Prod., 62 (12): 1632-1635). Insecticidal compounds with a closely related core structure were isolated from Aglaia roxburghiana and are described in WO 9604284 for use as active ingredients in agrochemical formulations.
New compounds (Compounds A and B), as described herein) have now been isolated from Aglaia leptantha, Miq. (Meliaceae) which uniquely possess a dioxanyloxy group at the 6-position of the cyclopenta[b]benzofuran core. Compounds A and B have been shown to exhibit potent cytotoxic and cytostatic effects on cancer cell growth and viability and thus the compounds of the invention and derivatives thereof, may be useful as therapeutic agents in the treatment of cancer and cancerous conditions or other diseases associated with cellular hyperproliferation.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word xe2x80x9ccomprisexe2x80x9d, and variations such as xe2x80x9ccomprisesxe2x80x9d and xe2x80x9ccomprisingxe2x80x9d, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
In a first aspect, the invention relates to compounds of Formula (I) or a salt or prodrug thereof. 
wherein
each R4-R10 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylacyl, optionally substituted cycloalkylacyl and a C-1 linked saccharide;
X is OR8 or NR9R10;
R11 and R12 are preferably each independently hydrogen or, alternatively, OR4 and R11, and/or OR5 and R12 together form a methylenedioxy group; and
Y is selected from the group consisting of optionally substituted phenyl, optionally substituted benzyl, optionally substituted benzoyl, optionally substituted C3-C8 cycloalkyl, (preferably optionally substituted C5-C6 cycloalkyl) optionally substituted CH2-(C3-C8 cycloalkyl) (preferably optionally substituted CH2-(C5-C6 cycloalkyl), optionally substituted 5-6 membered heterocyclyl, and optionally substituted CH2-(5-6 membered heterocyclyl).
In a preferred embodiment, the invention relates to compounds (including steroisomers within the dioxanyl group) of formula (i) or a salt or prodrug thereof. 
wherein
and each R1-R10 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted cycloalkylalkyl, optionally substituted arylacyl, optionally substituted cycloalkylacyl and a C-1 linked saccharide; and
X is OR8 or NR9R10);
R11 and R12 are each independently hydrogen or, OR4 and R11, and/or OR5 and R12 together form a methylenedioxy group. In one preferred embodiment, R11 and R12 are both hydrogen.
In one preferred embodiment, compounds of the present invention have the Formula (ii): 
or a salt or prodrug thereof.
Formula (ii) has 4 chiral centres in the dioxanyl moiety. Two isomers (isomeric in the dioxanyl group) of Formula (ii) have now been isolatedxe2x80x94Compounds A and B as described in Example 1.
In another aspect, the invention provides a composition comprising a compound of Formula (I), such as Formula (i), or a salt or prodrug thereof, together with a pharmaceutically acceptable carrier, excipient or diluent.
In still a further aspect, the present invention provides a method for the treatment of cancer or a cancerous condition or a disease state or condition associated with cellular hyperproliferation comprising the administration of a treatment effective amount of a compound of Formula (I), such as Formula (i), or a salt, derivative or prodrug thereof, to a subject in need thereof. Some particular cancerous conditions which may be treated by the compounds of the invention may include lung, prostate, colon, brain, melanoma, ovarian, renal and breast tumours and leukemia. Disease states or conditions associated with cellular hyperproliferation which may be treated by compounds of the invention may include atherosclerosis, restinosis, rheumatoid arthritis, osteoarthritis, inflammatory arthritis, psoriasis, peridontal disease or virally induced cellular hyperproliferation.